Role of Side-Chains in Forming Peptide Aggregates and Fibrils. IR and VCD Spectroscopic Studies. Theory and Experiment

Abstract

Formation of peptide aggregates and fibrils must ultimately be driven by interactions of side chains. Typically the lower solubility of hydrophobic sequences favors desolvation by formation of interchain contacts which are then stabilized further by various means. One way is development of ordered interdigitization of the side chains, which is particularly evident in poly-glutamic acid at low pH. The Glu side chain -COOH groups form bifurcated H-bonds with the amide C=O groups that are cross-strand H-bonded in what is termed a β2 sheet. This extra H-bond interaction leads to large shifts of the amide I vibrational frequencies and formation of stacked arrays of β-sheets. In other systems, hydrophobic interactions can results in similar stacking interactions. Vibrational spectroscopic methods have been used to establish β-sheet structures underlying many of these and isotope labeling has been used to differentiate parallel vs. antiparallel forms. Our DFT-based calculational model of β-sheet vibrational spectra was originally based on Ala-oligopeptides, forming normal β1 sheets, and focused on IR, VCD, and Raman spectra for isolated and stacked sheet structures, with variations in structure, alignment of strands, isotope labeling, twisting of single sheets and relative rotation of multiple sheets in the stack. In particular, our analyses of the spectra of Glu10 based peptides that form β2 sheets, are shown to be antiparallel but out of register by one residue, most likely in a step-wise pattern. Alternate (Glu-Aaa)n variants, where Aaa is a hydrophobic residue, can also show this pattern of intersheet side-chain intercalation. We extended these calculations by computing IR and VCD for Glun structures along MD trajectories that show evidence of sidechain ordering in qualitative agreement with experiment.